This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The UCSF PMT Project is a multi-disciplinary research program focused on the pharmacogenetics of membrane transport proteins that play a role in drug response pathways. The project seeks to understand the genetic basis for variation in drug response for drugs which interact with membrane transport proteins. This class of proteins is of great pharmacological importance as it provides the target for many commonly used prescription drugs and is a major determinant of the absorption, distribution and elimination of many clinically used drugs. This project seeks to test the hypothesis that variations in the DNA sequence of genes encoding membrane transporters underlie inter-individual differences in response to such drugs. To accomplish this, the program is structured around six interacting cores: genomics, cellular phenotyping, clinical phenotyping, biostatistics, shared resources/collaborations, and bioinformatics. The project also facilitate studies by contributing data to the publicly available knowledge base, PharmGKB (http://www.pharmgkb.org/), and to dbSNP (http://www.ncbi.nlm.nih.gov/projects/SNP/). The overall aims of the PMT project are to: a) Identify sequence variants in membrane transporter genes in the SLC and ABC superfamilies. b) Determine cellular phenotypes for transporter variants through experimental and computational methods. c) Determine the biological relevance of variants in membrane transporters to clinical drug response. d) Deposit the data in PharmGKB and develop shared resources for the pharmacogenetics research community. In this collaborative project, we are developing new methods for data collection and analysis of these experiments. This includes developing automated methods to store, analyze, summarize, and disseminate to researchers the genomic, cellular, and clinical data. We work closely with the Genomics Core (GC) developing data communication and transfer protocols that enable them to efficiently package and transmit to us genotype data for individual samples and sample pools. We also develop web-based tools that the GC uses to perform the transfer and that provide real-time data validation. The data transfer tools communicate with an automated data processing pipeline, which performs further validation. We develop, test, and implement software tools to analyze the data and summarize the analysis results from multiple perspectives and at various granularities. We work with the PMT investigators to identify additional analyses, both for ad hoc implementation and for incorporation into the high-throughput analyses. The results of all analyses are communicated rapidly to PMT and other investigators in tabular and graphical forms via programmatically constructed web pages. We maintain a public web site that provides summary results, including genetic variant frequencies by ethnicity. We also maintain an intranet, available only to PMT investigators, which includes detailed, per-sample data. At the appropriate time, we transmit the data to the PharmGKB database at Stanford University. The web sites also contain information on the program activities, including data and analysis on transporters currently under study. The PMT public website, password-protected intranet, database, and data processing pipelines are hosted by the RBVI. Nearly 100 million nucleotides of sequence data have been collected from 129 transporters, resulting in more than 3000 variants. For additional details see http://pharmacogenetics.ucsf.edu/